title: Tracking changes in the vraSR and graSR two component regulatory systems during the development and loss of vancomycin non-susceptibility in a clinical isolate.
abstract: We investigated changes in regulatory genes, vraS and graR, during development of vancomycin non-susceptibility in a patient with methicillin-resistant Staphylococcus aureus who failed therapy and following in-vitro vancomycin exposure and a subsequent drug-free growth period. Minimum Inhibitory Concentration (MICs) were determined and genes sequenced at each stage. After 30 days of vancomycin exposure, the strain attained maximum MIC (20 mg/L) and was resistant to all antibiotics. Reversion to vancomycin susceptibility occurred 21 days after removal. We observed mutations in vraS and graR during non-susceptibly development and novel stop codons in the reverted strain. Mutations in graR appear important for development of intermediate susceptibility to vancomycin. The results suggest that monitoring of vancomycin therapy could allow earlier change to appropriate agents.
authors.affiliation: Health Technology and Informatics Department, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
authors.forename: V C
authors.initials: VC
authors.lastname: Doddangoudar
authors.forename: M V
authors.initials: MV
authors.lastname: Boost
authors.forename: D N C
authors.initials: DN
authors.lastname: Tsang
authors.forename: M M
authors.initials: MM
authors.lastname: O'Donoghue
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000382:microbiology; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C478170:VraR protein, Staphylococcus aureus; C478169:VraS protein, Staphylococcus aureus; D014640:Vancomycin